DESCRIPTION: The goal of the proposed project is to develop a biocompatible ultrafine particle-based vector system for the intranasal delivery of clozapine for the pharmacological therapy of treatment- resistant schizophrenic disorders and their associated suicidal behavior. The rationale behind the use of intranasal clozapine is grounded on the observation of clozapine's extensive first- pass metabolism associated with buccal intake, clozapine's extensive binding to plasma proteins, its short elimination half-life, the absence of significantly active metabolites, and the potentially serious side effects brought about by the high oral doses required for therapeutic benefit. The LNK Chemsolutions LLC/University of Chicago team will use a series of particle design tools, in vivo, ex vivo and in vitro methods to develop the seminal Phase-I level research. Electrohydrodynamic methods will be used to design particles with well-defined sizes and drug payloads, using three different polymers. In vitro drug release examinations will be complemented by muco-adhesive tests, and ex vivo (swine nasal membrane) drug permeation studies. These will guide in vivo (mouse model) studies aimed at elucidating particle and drug transport.